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696
Mini-Reviews in Medicinal Chemistry, 2015, 15, 696-704
Multitarget Network Strategies to Influence Memory and Forgetting: The
Ras/Mapk Pathway as a Novel Option
Márton Dávid Gyurkó1,*, Attila Steták2, Csaba Sőti1 and Péter Csermely1
1
Semmelweis University, Department of Medical Chemistry, Molecular Biology and
Pathobiochemistry, Budapest, Üllői út 26, 1085 Hungary; 2University of Basel, Department of
Molecular Neurosciences, Basel, Switzerland
Abstract: The Ras/mitogen activated protein kinase (MAPK) pathway has key importance in
development, cell differentiation and senescence, tumorigenesis, learning and memory. The clinical
manifestations associated with this highly conserved pathway are called RASopathies. Phenotypic
features are diverse and overlapping, but cognitive impairment is a common symptom. Here, we
propose an approach based on molecular networks that link learning, memory and forgetting to the
M.D. Gyurkó
RASopathies and various neurodegenerative and neurodevelopmental diseases such as Alzheimer's
disease, Parkinson's disease and autism spectrum disorders. We demonstrate the cross-talks of the molecular pathways in
RASopathies and memory and the role of compartmentalization in these processes. The approved drugs are also overviewed,
and C. elegans is proposed as a viable model system for experimental exploration and compound target prediction.
Keywords: Learning, memory, molecular networks, neurodegenerative disorders, Ras/MAPK, RASopathies.
1. INTRODUCTION
The Ras/mitogen activated protein kinase (MAPK)
pathway is an evolutionary conserved signaling pathway that
has been associated with development, cell differentiation
and senescence, tumorigenesis, learning and memory. Being
one of the most studied pathways [1], the sheer number of
experimental results requires systems level approaches [2] to
tackle the complexity of the dataset.
Molecular networks include gene regulatory and gene coexpression networks, protein-protein interaction networks,
protein co-phosphorylation networks, metabolic and
signaling networks. A common theme is that the multivariate
equilibrium of reactions and pathways can be meaningfully
simplified to visualizable and understandable models. This is
especially useful, where not only single interactions, but the
co-dependent system of multiple reactions and interactions
has to be considered during pharmaceutical lead design,
exploration of mechanism of action and toxicity prediction.
All the above mentioned networks are well established
tools for specific fields (genetic studies, proteomics,
phosphoproteomics, metabolomics, respectively), but the
combination of metabolic and signaling networks may
represent the interactions of arbitrary molecules (DNA,
RNA, proteins, ‘even’ anorganic molecules) to form biologically
meaningful, canonical pathways. This is an additional level
of organized knowledge above simple interactions. These
networks can also explain complete signaling cascades and
include all relevant molecule types (enzymes, transporters,
*Address correspondence to this author at the Semmelweis University,
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry,
Budapest, Üllői út 26, 1085 Hungary; Tel: +36 20 914 70 68;
E-mail: [email protected]
1875-5607/15 $58.00+.00
ion channels and ion levels, receptors, just to name a few)
that can be targeted in pharmaceutical exploration in
medicinal chemistry.
In this review we focus on results in H. sapiens because
animal and cell culture models have been widely covered
elsewhere [3-8].
Section 2 outlines a schematic network representation of
the Ras/MAPK pathway and its cross-talks to pathways
associated with learning and memory. Section 3 provides
insights regarding the compartmentalization of the Ras/
MAPK pathway. Section 4 details the related pathological
conditions, section 5 proposes novel pharmacological strategies,
and section 6 suggests C. elegans as a model system for the
research of the Ras/MAPK pathway, learning and memory.
Lastly, section 7 summarizes the novelties of this review.
2. THE MOLECULAR NETWORK OF Ras/MAPK, IP3/
DAG/PKC, cAMP/PKA, Ras/PI3K PATHWAYS AND
THE VARIOUS FORMS OF Ca2+ SIGNALING
Signaling pathways are often bridged by cross-talks that
allow the orchestrated regulation of multiple processes. Such
biological complexity is beyond intuitive understanding, but
network science provides well established methods to
represent, simplify and elucidate complex systems. Molecular
networks consist of nodes and edges: nodes can be arbitrary
molecules such as proteins, metabolites, RNA, etc., and
edges are physical, biochemical or functional interactions
among these.
Fig. (1) demonstrates a neuron specific subnetwork of the
Ras/MAPK pathway and the most important pathways
involved in learning and memory formation.
© 2015 Bentham Science Publishers
Multitarget Network Strategies to Influence Memory and Forgetting
Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 8
GPCR
Synapse
Gi
AMPAR
NMDAR
Gs
NTRK1
GFRs
GRB2
Gq
SHC1
ADCy1
PLCb
Plasma membrane
SYNGAP1
DAG
CALM
GRF1
697
SOS1
RAS
CNrasGEF
PTPN11
NF1
RASA1
RASA2
RASA3
RASA4
SHOC2
cAMP
PP1c
CAMK2
Cytoplasm
Ca2+
PKC
RAP
IP3
Endoplasmic reticulum
RAF
PI3K
MEK
Cytosk.
ERK
SPRED1
PKA
IP3R
ATP2A2
PLN
UCHL1
IPO7
ERK
Nucleus
RSK2
PKA
DNA
CREB
CBP
Fig. (1). Schematic network representation of Ras/MAPK, IP3/DAG/PKC, cAMP/PKA, RAS/PI3K pathways, Ca2+ signaling and their
interactions in neurons.
The network of the figure was manually assembled from
publications (see the references in the text) and the KEGG
pathway database (Release 71.0, July 1, 2014) [9]. Canonical
names of the nodes with their abbreviations are listed in the
text, 'Cytosk.' refers to cytoskeletal changes, 'Synapse' refers
to synthesis of synaptic proteins. The network contains
simplifications to enhance lucidity. Arrow-headed lines
denote activation while bar-headed lines represent inhibition.
Network visualization was performed using Cytoscape 3.0
[10] and GIMP 2.8 (http://gimp.org).
Receptor tyrosine kinases (RTK) can activate RAS
through the signaling complex containing growth factor
receptor bound protein 2 (GRB2), SHC-transforming protein
1 (SHC1) and son of sevenless homolog 1 (SOS1), which
leads to the phosphorylation of the Raf kinase (RAF), the
mitogen-activated protein kinase kinase 1 (MEK) and the
extracellular regulated kinase I/II (ERK 1/2). ERK
translocates to the nucleus to modulate gene expression
through 90 kDa ribosomal protein S6 kinase (RSK2) and the
cyclic AMP-dependent transcription factor (CREB) 1 and 2.
Calcium signaling plays a central role in synaptic
plasticity, learning and memory. Elevations in intracellular
calcium level can lead to the activation of Ras in various
ways [11-15]. Some of the calcium-dependent signaling
mechanisms act on a short time scale, while others invoke
more permanent responses via the facilitation of protein
synthesis.
N-methyl-D-aspartate receptors (NMDAR), key elements
of long-term potentiation, can induce direct Ca2+ influx,
while Gq protein-coupled receptors can induce increased
intracellular Ca2+ levels by the activation of phospholipase
C-beta (PLCb). PLCb triggers inositol-(1,4,5)-trisphosphate
(IP3)/diacyl-glycerol (DAG) signaling, and IP3 releases Ca2+
from the endoplasmic reticulum. Both signaling pathways
converge on the members of protein kinase C (PKC), a
protein family associated with emotional memory and posttraumatic stress disorder [16]. PKC can then activate both
Ras and Raf.
Increased intracellular Ca2+ levels facilitate the exchange
of the Ras-bound GDP to GTP by the Ras-specific guanine
nucleotide-releasing factor 1 (GRF1), which leads to
activated downstream signaling through Raf.
The propagating Ca2+ transient can be re-strengthened
from the endoplasmic reticulum by IP3 receptor-mediated
Ca2+ release, and upon reaching the nucleus the Ca2+
transient can facilitate gene transcription through CREB, a
cross-road for multiple pathways including Ras/MAPK [17].
698 Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 8
Members of the Kv4 type potassium channel family
regulate local membrane depolarization. ERKs can
phosphorylate channel components, which leads to stronger
depolarization and ultimately to the activation of more
NMDARs [18]. This is a rapid, protein synthesis-independent
mechanism involving Ca2+, K + and Ras/MAPK signaling.
Gs-coupled protein receptors facilitate, while Gi-protein
coupled receptors inhibit adenylate cyclase type 1 (ADCY1),
the enzyme known for converting adenosine triphosphate to
cyclic adenosine monophosphate (cAMP) in neurons. ADCY1
is calcium/calmodulin dependent, therefore it is coupled with
the above detailed calcium signaling.
cAMP can regulate the Ras/MAPK pathway either in a
PKA-dependent or in a PKA-independent manner [19-20].
During the PKA-dependent process the PKA regulatory
subunits bind cAMP, which leads to the opening of the
active sites of the catalytic subunits, and the consequent
dissociation of the PKA complex. The catalytic subunits can
phosphorylate Ras-specific guanine nucleotide-releasing
factor 1 (GRF1), upon which GRF1 facilitates the GDP-GTP
exchange of Ras. The active PKA catalytic subunits can also
translocate to the nucleus to phosphorylate CREB2 and
induce the expression of gene cascades.
In the PKA-independent pathway cAMP can bind directly
to CNrasGEF, a guanine nucleotide exchange factor that
facilitates the GDP-GTP exchange of Ras to increase its
downstream activity. The exact details of these processes are
not completely explored yet. This is interesting all the more,
since the cAMP/PKA pathway is a highly studied signaling
pathway in neurons.
PKA inhibits phospholamban (PLN) too, which is a
negative regulator of the Ca2+ transporting ATPase isoform 2
(ATP2A2) in the membrane of the sarcoplasmic/endoplasmic
reticulum. If ATP2A2 is released from PLN inhibition, it
transports Ca2+ to the endoplasmic reticulum and downregulates
the cytoplasmic Ca2+ signal.
Ras isoforms are major convergence points of the above
mentioned signaling processes (see also Fig. 1). KRas, HRas
and NRas are interacting partners of the phosphatidylinositol
4,5-bisphosphate 3-kinase (PI3K), which contributes to the
regulation of the actin cytoskeleton. Glutamate stimulation
was shown to alter the dendritic spine volume through Ras
[21], and it was found recently that the synaptic actin
dynamics play essential role in forgetting too [22].
The large number of cross-talks between the Ras/MAPK,
the IP3/DAG/PKC, the cAMP/PKA, the Ras/PI3K pathways
and the various forms of Ca2+ signaling stress the importance
of neuron-specific experimental data collection and their
representation as molecular networks. The latter are required
on two levels: large-scale networks should provide integrated
data sources, from which small-scale, high resolution, focused
networks can be built. SynSysNet, a synaptic interaction
network [23] is a great step forward in that direction.
3. THE ROLE OF SUBCELLULAR COMPARTMENTALIZATION IN THE Ras/MAPK PATHWAY
Molecular events of learning and memory involve a large
number of subcellular compartments and extracellular
Gyurkó et al.
localizations. This allows enhanced temporal and spatial
regulation, creates function-specific microenvironments and
enables synapse-specific learning [15, 24-25], but requires
the trafficking of signaling molecules, often on long distance
from the synapses to the nucleus.
Synaptic NMDARs (see Section 2) and neuronal growth
factor receptors (see Section 4), for example, can trigger Ras,
which translocates Raf to the plasma membrane [26] and
leads to the phosphorylation of MEK. MEK phosphorylates
ERK, then dissociates from it, which is required for the
nuclear translocation of ERK [27]. ERK 1/2 is thought to
enter the nucleus through the nuclear pore complexes with
the help of importin-7 (IPO7) or in an importin-7independent manner [28-30], but more details are needed to
fully elucidate the mechanisms of these translocations.
Ca2+ influx through voltage-dependent calcium channels
and NMDARs can lead to activity-dependent gene expression
in neurons [17, 31]: calcium/calmodulin-dependent protein
kinase IV mediates rapid nuclear CREB phosphorylation,
while calcium/calmodulin-dependent protein kinase II
(CAMK2) facilitates the Ras/MAPK pathway and initiates a
slower, but more long-lasting CREB activation. CREB is
therefore a convergence point for these two gene-regulating
pathways [32].
Protein kinase A is a central enzyme in learning- and
memory-related processes. The activated catalytic subunit of
PKA also translocates to the nucleus by diffusion to facilitate
transcription through CREB [33].
Protein synthesis on the other hand is not restricted to
perinuclear localizations. RNA trafficking enables spatially
restricted, local translation in response to stimulation [34].
mRNAs are transported rapidly and bidirectionally in large
granules together with RNA-binding proteins, ribosomes and
translational factors [35].
These examples highlight that new experimental methods
and much more subcellular localization data are needed to
link the translocation mechanisms to behavioral phenotypes
in learning and memory formation [8].
4. PATHOLOGICAL CONDITIONS ASSOCIATED
WITH THE Ras/MAPK PATHWAY: RASOPATHIES
RASopathies are clinically defined diseases caused by
germline mutations in genes that encode proteins of the
Ras/MAPK pathway [36, 37]. Known RASopathies are listed
in Table 1. Each disorder has a unique set of phenotypic
features, but due to the underlying common pathway, many
of these are overlapping including characteristic facial
features, cardiac defects, cutaneous abnormalities, and a
predisposition to malignancies and varying degree of
neurocognitive impairment.
Guanine nucleotide exchange factors (GEFs: GRF1,
CNrasGEF on Fig. 1) upregulate, GTPase activating proteins
(GAPs: NF1, RASA1, RASA2, RASA3, RASA4,
SYNGAP1 on Fig. 1) downregulate downstream Ras
signaling. Mutations in the genes encoding either GEFs or
GAPs both can cause neurocognitive impairment [8] or even
enhanced verbal memory at the cost of impaired visual and
Multitarget Network Strategies to Influence Memory and Forgetting
Table 1.
Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 8
699
Pathological conditions associated with the members of the Ras/MAPK pathway: known RASopathies.
Name of the condition
Affected pathway member
Cognitive impairment*
References
Autoimmune lymphoproliferative syndrome
FAS, KRAS, NRAS
No
[36, 38]
Capillary malformation-AV malformation (CM-AVM)
syndrome
RASA1
Secondary
[36, 39, 40]
Cardio-facio-cutaneous (CFC) syndrome
BRAF, MAP2K1, MAP2K2, KRAS
Yes
[36, 37, 41, 42]
Coffin-Lowry syndrome **
RSK2
Yes
[43]
Costello syndrome
HRAS
Yes
[37, 44, 45]
Hereditary gingival fibromatosis type I
SOS1
No
[37, 46-48]
Legius syndrome
SPRED1
Yes
[49-52]
LEOPARD syndrome
SHP2, RAF1, BRAF
Yes
[53-57]
Neurofibromatosis type I (Von Recklinghausen disease)
NF1
Yes
[58-63]
Noonan syndrome
PTPN11, SOS1, RAF1, KRAS, NRAS, BRAF
Yes
[64-67]
*Symptoms of RASopathies are diverse and overlapping, therefore the cognitive impairment column denotes only the possibility to develop varying degree of any cognitive
symptom, not a mandatory condition.
**Coffin-Lowry syndrome is not reckoned among RASopathies, but it is related to the 90 kDa ribosomal protein S6 kinase 1, a target of ERK.
working memory [68-69], suggesting that a fine balance and
tight regulation of the Ras/MAPK pathway is necessary for
healthy cognition.
How can some RASopathies show neurocognitive
impairment, while others, involving the very same gene(s),
do not? For example, mutation in the SOS1 gene has been
found both in Noonan syndrome and hereditary gingival
fibromatosis type 1, but only patients with Noonan syndrome
have learning difficulties. Tissue specificity of the protein
isoforms is a possible explanation: the KRAS mutation in
cardio-facio-cutaneous syndrome is expected to be less
tissue specific compared to the B and T-lymphocyte
specificity in autoimmune lymphoproliferative syndrome.
The interacting partners of affected proteins can vary among
tissues and subcellular compartments as well, causing
differences in regulation, which further emphasizes the need
for network-based approaches.
Such interactions of the Ras/MAPK pathway show crosstalks with other neurodegenerative diseases (see Fig. 1). The
cognitive and memory dysfunction in Alzheimer's disease is
thought to be caused by amyloid-beta plaques and tau
protein tangles. ERK negatively regulates the expression of
beta-secretase, a precursor enzyme of amyloid-beta plaques
[70]. Tau is hyperphosphorylated in the tangles, and ERK
and MEK have been shown to phosphorylate tau [71].
Alpha-synuclein, ubiquitin carboxyl-terminal hydrolase
L1 (UCHL1) [72] and Leucine-rich repeat kinase 2 (LRRK2)
are proteins encoded by 3 of the 9 genes associated with
Parkinson's Disease. Increased alpha-synuclein level is
suggested as a consequence of Ras/MAPK dysfunction [73].
UCHL1 cross-talks with the Ras/MAPK pathway [6, 74].
LRRK2 also has a Ras/GTPase superfamily-like domain
[75], although no relation with the Ras/MAPK pathway has
been revealed. 3,4-dihydroxyphenyl-L-alanine (L-DOPA) is
the most effective and commonly used treatment in
Parkinson's disease. It can cause L-DOPA induced
dyskinesia through protein kinase A targets [76], among
which there are members of the Ras/MAPK pathway (see
Section 2).
High affinity nerve growth factor receptor (NTRK) 1 and
2 are receptors of the brain-derived neurotrophic factor
(BDNF), which regulates directly the growth factor receptorbound protein 2 (GRB2). BDNF is linked to learning and
memory [77], autism [78] and depression models [79-80].
Autism traits are also associated with RASopathies [81].
The network and the pathological conditions were
manually assembled from publications (see the references in
the text of Section 2, 4, and 5), network insertion of drugs
was manually curated using the DrugBank database (release
4.0, 1st January 2014) [82]. Rectangles in the middle of the
figure mark signaling proteins of the Ras/MAPK pathway,
ellipses on the right mark Ras-dependent pathological
conditions (RASopathies), while octagons on the left
indicate drugs affecting Ras/MAPK-depedent signaling.
Arrow-headed lines denote activation while bar-headed lines
represent inhibition. Network visualization was performed
using Cytoscape 3.0 [10] and GIMP 2.8 (http://gimp.org).
5. NETWORK-BASED COMPOUND DESIGN
Members of the Ras/MAPK pathway were identified as
drug targets with the help of their UniProt protein identifiers.
The drugs were collected from DrugBank and the result set
was filtered to approved drugs and was verified manually
from publications.
700 Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 8
Gyurkó et al.
Ras/MAPK Pathway
Drugs
GRB2
Dabrafenib
Diseases
Noonan
PTPN11
SOS1
Costello
Vemurafenib
RAS
RAF
Sorafenib
SPRED1
LEOPARD
MEK
Regorafenib
Legius
ERK
ERK
Bosutinib
CFC
RSK2
Tratmetinib
Coffin-Lowry
CREB
CBP
Fig. (2). FDA-approved drugs and the pathological conditions associated with the Ras/MAPK pathway.
Table 2.
Approved drugs targeting the proteins of the Ras/MAPK pathway according to the DrugBank database (release 4.0, 1st
January 2014 [82]). See also Figure 2.
Drug name
Target protein
Mechanism of action
DrugBank ID
Bosutinib
MEK1, MEK2
Unknown
DB06616
Dabrafenib
BRAF, CRAF
Kinase inhibitor
DB05190
Regorafenib
BRAF, CRAF
Kinase inhibitor
DB08881
Sorafenib
BRAF, CRAF
Kinase inhibitor
DB08553
Trametinib
MEK1, MEK2
Kinase inhibitor
DB08911
Vemurafenib
BRAF, CRAF
Kinase inhibitor
DB00398
The FDA-approved drugs targeting the Ras/MAPK
pathway are listed in Table 2. All of them are anticancer
compounds, which have two current implications for
RASopathies. First, cancer treatment with the above
mentioned drugs may lead to RASopathy-like symptoms,
and indeed there is a report of vemurafenib treatments,
where cutaneous adverse effects were overlapping with the
symptoms of RASopathies [83]. Second, a widely
experienced adverse effect of anticancer treatment is the
long-lasting cognitive dysfunction [84]. Taken together the
following 3 leads (1) the Ras/MAPK pathway is involved in
the molecular processes of learning, memory and forgetting
[85-89]; (2) the aforementioned anticancer compounds target
the members of this pathway, and (3) the adverse effects of
the anticancer treatment overlap with the symptoms of
RASopathies [83], here we propose that the link between
Ras-dependent anti-cancer treatment-induced cognitive
dysfunctions and the cognitive impairment observed in
RASopathies should be experimentally explored.
Multitarget Network Strategies to Influence Memory and Forgetting
There are no approved drugs for the causal treatment of
RASopathies. The requirements for such compound would
include reversibility, capability to cross the blood-brain
barrier, and probably the ability to target multiple members
or regulators of the involved pathways. Ras itself is difficult
to target [90]. This example shows that targeting single,
central molecules with many interactors (e.g. signaling hubs,
such as Ras) may have a strong effect, but the molecular
perturbations may also spread widely due to the large network
neighborhood and may cause side effects or toxicity [91].
It has been proposed that multitarget approaches based
on molecular network analysis may allow a fine-tuned
modulation of the required pathways instead of their
complete blockade, and may also overcome drug resistance
by downregulating redundant pathways [91-95]. This
strategy was recently successfully applied to KRAS [96].
Various combinations of compounds activating serotonin
and/or dopamine receptors were also found to moderately
enhance the Ras-PI3K/PKB signaling input in mice [97].
This suggests that combination therapy, e.g. multitarget
„cocktail drug treatment” with already approved drugs or
new compounds is an option worth exploring. Multi-targetdirected drug design strategies are actively explored areas in
medicinal chemistry [98].
Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 8
701
In summary, C. elegans is a simple, yet representative
model system that may provide valuable insights into the
shared molecular properties of RASopathies, various
neurodegenerative diseases and their relation to the
fundamentals of learning and memory [107].
7. SUMMARY
The Ras/MAPK pathway is an important signal
transduction and convergence pathway in the regulation of
synaptic proteins, active in both long-term potentiation and
in the modulation of dendritic spine volume. Here we
presented the Ras/MAPK, IP3/DAG/PKC, cAMP/PKA,
Ras/PI3K pathways and the various forms of Ca2+ signaling
as an interconnected network in neurons. This is the first
time to our best knowledge that pathways involved in
learning and memory are associated with the Ras/MAPK
pathway in a focused, network-oriented approach also
considering tissue and intracellular compartment-specificity.
Neurodegenerative and neurodevelopmental disorders are
diseases with diverse molecular background, therefore the
affected molecular networks and biomarker patterns should
be identified to understand the systems level pathomechanisms
and to achieve definitive diagnostic criteria.
Network analysis can highlight promising drug targets
[91, 99]. For example, even a pilot analysis of the molecular
network in (Fig. 1) reveals that Raf has the highest
betweenness centrality, a measure often associated with
importance in signal transmission [100]. Raf is also the
target of the highest number of approved drugs among the
members of the Ras/MAPK pathway. In-depth analyses need
larger, more detailed, neuron-specific signaling networks
that also take into consideration regulators and key players
of subcellular translocation as compound targets.
Reviewing Ras/MAPK-related pathological conditions
(RASopathies) we proposed the first time that the cognitive
dysfunction caused by anticancer drugs targeting the
Ras/MAPK pathway might have common molecular roots
with RASopathies. Compound design for these conditions is
challenging due to the highly regulated and central nature of
the Ras/MAPK pathway, thus tissue-specific, network-based,
multitarget approaches might be options for in silico
exploration. Finally, C. elegans might be a viable model
system for early experimental validation.
6. C. ELEGANS AS A MODEL SYSTEM FOR Ras/
MAPK SIGNALING, LEARNING AND MEMORY
CONFLICT OF INTEREST
The most common animal model systems for
RASopathies include M. musculus [36], D. rerio [101] and
D. melanogaster [102]. De novo synapse formation is part of
the synaptic plasticity in all these organism, which is an
additional level of complexity.
The well explored wiring diagram of the 302 neurons in
C. elegans [103] does not change in mature animals,
synaptic plasticity is therefore restricted to the changes of the
synaptic strength. The Ras/MAPK pathway and fundamental
molecular processes of learning and memory are both
evolutionary conserved and have been found in C. elegans.
There is a wide range of established molecular biological
tools for C. elegans, the worm has a short lifespan, and the
laboratory conditions of related experiments are also
economic. The phenotypic characterization of C. elegans
orthologues of known human disease genes, proteins or drug
targets may lead to a better understanding of the underlying
molecular processes [104, 105]. In reverse: mapping of
genes, proteins or processes explored in C. elegans to their
human orthologues may highlight novel targets for
experiment design or early compound target discovery in H.
sapiens [106].
The author(s) confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
Authors acknowledge the helpful advice of members of
the LINK Research Group (http://linkgroup.hu/) and the
Stress Research Group (http://stressgroup.semmelweisuniv.hu/) of the Semmelweis University. Work in the
authors’ laboratory was supported by research grants from
the Hungarian National Science Foundation (OTKAK83314), from the Forschungsfonds of the University of
Basel (DPE2112) and by a fellowship from the Gedeon
Richter Centennial Foundation (MDG).
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Revised: October 27, 2014
Accepted: November 12, 2014